Most drugs used to treat microbial infections are given more than once during a dosage regimen. The objectives during antimicrobial therapy are to maximize blood concentration, preferably several fold higher than the minimum inhibitory concentration (MIC) for the particular agent, but to minimize both the risk of toxicity to the patient and of promoting microbial resistance. Although oral administration will be the preferred route, in the case of antibiotics this route is frequently unattractive because of their low or variable oral bioavailability. In addition extremely high plasma concentrations of antibiotics are frequently required to achieve their MIC values towards certain gram-negative bacteria. (Antibiotic and Chemotherapy: Anti-infective agents and their use in therapy, 7th edition, Ed. by O'grady F., Finch R. G., Lambert H. P., Greenwood D.; Churchill Livingstone, 1997).
While many compounds are known to be useful as pharmacologically active substances, some of them have relatively short biological half-life and need to be administered several times a day in order to achieve desired therapeutic effect. However, a decrease in the frequency of administration will not only reduce the burden on the patient but will also increase compliance and thus provide greater therapeutic effect. It can be achieved by controlling the release of active ingredients, so that the effective level is maintained in the blood for a prolonged period of time or by reducing the elimination of the active from the body thereby increasing its concentration in blood resulting in its retention in blood for longer period.
This has been primarily achieved by development of new drug delivery systems utilizing diverse techniques and principles. Amongst these, known in the art is one such delivery system, which employs the use of pH dependent and pH independent polymers. The present invention uses a combination of methacrylic acid copolymers wherein one controls the release of the drug in acidic media and the polymers, which are essentially pH independent control the release at later stage. Control of the rate of release can produce constant blood levels of the active ingredient that may result in reducing the frequency of administration, thereby improving patient compliance to the dosage regimen.
Many drugs and drug metabolites are actively secreted by the proximal tubular active transport mechanism and interactions may arise from competition for these systems. Particularly with antibiotic therapy, active tubular secretion is a significant route of elimination. Drugs that use the same active transport system in the kidney tubules can compete with one another for secretion. Probenecid belongs to this class of drugs, which is able to compete successfully with some other drugs for an active secretion mechanism in the kidney tubule. This prevents them from being secreted into the tubular filtrate. Probenecid is later passively reabsorbed from the kidney tubules. Probenecid was extremely useful in the early days of penicillin when the combination raised and prolonged penicillin plasma levels. Inhibition of the urinary excretion of penicillin and some cephalosporins has been used as a device to increase the biliary excretion of these agents, thereby raising the antibiotic concentrations in the biliary tract. This has been used to improve the efficacy of antibiotic treatment (Antibiotic and Chemotherapy: Anti-infective agents and their use in therapy, 7th edition, Ed. by O'grady F., Finch R. G., Lambert H. P., Greenwood D.; Churchill Livingstone, 1997).
Cefuroxime, as disclosed in British Patent No. 1453049, is a valuable broad spectrum antibiotic characterized by high activity against a wide range of gram-positive and gram-negative microorganisms. Antibiotics for oral administration should be in a form which provides high bioavailability, whereby absorption into the blood from the gastro-intestinal tract (GIT) is maximized. However, when cefuroxime is administered orally, it is poorly absorbed in the GIT hence it is administered parenterally.
U.S. Pat. No. 4,267,320 discloses that esterification of carboxyl group of cefuroxime to 1-acetoxyethyl ester i.e. cefuroxime axetil enhances absorption of cefuroxime from GIT where upon esterifying group is hydrolysed by enzymes present in human body.
Pure cefuroxime axetil can be produced in crystalline form or amorphous form. U.S. Pat. No. 4,820,833 discloses that amorphous cefuroxime axetil is more stable with increased absorption via GIT and has a correspondingly high level of bioavailabilty on oral or rectal administration.
U.S. Pat. No. 4,897,270 discloses a film coated cefuroxime axetil tablet to mask the bitter taste of the active upon oral administration. The patent teaches that conventional film coated tablets result in low levels of absorption of cefuroxime axetil from GIT and this is overcome by control of the film coat rupture time and use of a tablet core which disintegrates immediately following rupture of the film coat. The patent further teaches that cefuroxime axetil once in contact with aqueous media can form a gelatinous mass. This gelling effect is temperature dependent but does occur at temperatures of about 37° C., i.e. at the physiological temperature at which the disintegration of orally administered tablets takes place. The relatively slow permeation of moisture from the film coat to the core, which occurs upon administration of the tablets provided with conventional film coats leads to gelling of cefuroxime axetil present in the core. The gel formation leads to poor disintegration of the tablet core and hence to poor dissolution of cefuroxime axetil, thus the absorption from the GIT is greatly reduced. This occurs with both the crystalline and amorphous form of cefuroxime axetil.
However, Patent Application No. WO 99/44614 criticizes that such thin film coating with the water soluble film-forming material cannot completely block the absorption of moisture into the core upon long term storage and thus rather may cause gelation of the active ingredient within the core of the tablet upon storage.
As an effort to prevent the gelation of the cefuroxime axetil particles, U.S. Pat. No. 4,865,851 discloses cefuroxime axetil composition comprising particulate cefuroxime axetil coated with an integral coating of a lipid or mixture of lipids which are insoluble in water and which serves to mask the bitter taste of cefuroxime axetil but disperses or dissolves on contact with gastro-intestinal fluid. The resulting particles can be incorporated into pharmaceutical compositions for oral administration, for example aqueous suspension, dry product for reconstitution with water or granules. However, the drawback is that coated particles having diameter of less than 250 microns are preferred and the coating procedure employed is rather elaborate, resulting in the process, which is inconvenient for preparing solid dosage forms of cefuroxime axetil for oral administration.
Patent Application No. WO 99/44614 discloses a pharmaceutical composition containing cefuroxime axetil, which is not gelled by moisture absorption and is thus stable during storage period comprising amorphous cefuroxime axetil and silicon dioxide or its hydrate as a microenvironmental pH adjustor and an anti-gelling agent for cefuroxime axetil.
Patent Application No. WO 99/08683 discloses a pharmaceutical composition comprising of a co-precipitate of cefuroxime axetil and a water-soluble excipient selected from the group consisting of povidone, hydroxy propyl cellulose, methylcellulose, lactose, mannitol and sorbitol. The co-precipitate is made by dissolving the active ingredient and the water-soluble excipient in a solvent or combination of solvents and evaporating the solvents. The solvents in which cefuroxime axetil and the excipient having relatively high solubility have been used so as to minimize the amount of solvent used.
Patent Application No. WO 99/62559 discloses a pharmaceutical tablet comprising cefuroxime axetil and a carbonate or a bicarbonate to enhance the rate of disintegration of the tablets in gastric fluid.
Patent Application No. WO 00/30647 discloses cefuroxime axetil in non-gelatinous form on contact with an aqueous liquid comprising cefuroxime axetil in the form of a solid solution in a polymer or in the form of a solid dispersion on an adsorbent, useful for pharmaceutical composition.
U.S. Pat. No. 5,580,578 discloses a stable solid controlled release formulation comprising an active coated with a plasticized aqueous dispersion of a hydrophobic acrylic polymer. The coated substrate is cured at a temperature greater than the glass transition temperature of the acrylic polymer used, for 24 to 60 hours to provide a stabilized dissolution of the active which is unchanged after exposure to accelerated storage conditions.
U.S. Pat. No. 5,578,316 discloses a taste masked pharmaceutical granular composition comprising a core material containing an unpleasant tasting drug having coatings of separate layers of aqueous dispersions of methacrylate ester copolymers providing an immediate release of the drug in the stomach.
As none of the prior arts summarized above provide a controlled release cefuroxime axetil composition, a need exists for such a composition wherein the active ingredient, cefuroxime axetil is released in a controlled manner maintaining therapeutically effective level in the blood such that the composition is suitable for once-daily administration thereby improving patient compliance to the dosage regimen.
Thus the object of the present invention is to provide a long acting pharmaceutical composition comprising controlled release cefuroxime axetil wherefrom the cefuroxime axetil is released in a manner such that the composition is suitable for once daily administration.
Another object is directed to controlling the release profile of the active ingredient, cefuroxime from the delivery system and thereby maintaining the blood levels for longer duration or controlling the release profile of the active coupled with use of selective_adjuvant which would reduce the elimination/excretion of the active ingredient from the body for further prolonging the blood levels to improve the efficacy of the composition.
Another object is directed to provide for a controlled release and formulation of cefuroxime axetil with maximum bactericidal activity and also provide desired serum levels that would continuously exceed the MIC of the pathogen and favour providing optimal dosing regimen.
Yet further object is directed to provide for a controlled release formulation of cefuroxime axetil which would enable continuously maintaining concentrations above a certain level related to the MIC for the specific pathogen and thus would be more efficacious than the high peak and trough concentrations obtained with an intermittent dosing regimen.
Further object of the present invention thus directed to provide a long acting pharmaceutical composition suitable for once daily administration comprising controlled release cefuroxime axetil optionally in combination with immediate release or controlled release probenecid, which would release cefuroxime axetil in a manner such that effective blood levels of cefuroxime are maintained for longer duration and elimination/excretion of cefuroxime from body is reduced by use of probenecid as an adjuvant thereby further extending effective blood levels of cefuroxime.
Yet further object of the present invention also aims at overcoming the limitation of gelling tendency of cefuroxime axetil by rapid disintegration of the tablet and still controlling the release of the drug by particulate coating whereby the composition would disintegrate in the stomach on contact with gastrointestinal fluid resulting in coated controlled-release granules with selective coating to release the active drug slowly over a desired period of time thus sustaining its therapeutic action.